HFrEF and Neurohormonal Systems

Transcription

1 HFrEF and Neurohormonal Systems Normal Control of the Circulation: Neurohumoral Balance Vasoconstrictor Salt and H 2 O retaining Vasodilator Diuretic Richard Troughton CSANZ Breakfast Symposium 15 June 218 Endothelin Angiotensin II Norepinephrine Urocortin Neurohormonal Imbalance in Heart Failure Sympathetic Nervous System: Role in the pathophysiology of HF Excess vasodilation Compensation Excess vasoconstriction Endothelin Angiotensin II Vasopressin Norepinephrine Urocortin HF is characterized by heightened sympathetic tone Imbalances in baroreceptor reflexes and AngIIdependent SNS activation play an important role in adverse haemodynamic and cardiac responses Stimulation of SNS in HF results in Heart rate Contractility Na reabsorption Renal and peripheral vascular resistance Direct myocardial toxicity Adapted from Shah M et al. Rev Cardiovasc Med. 21;2(suppl 2):S2 S6. Ach=acetylcholine; AngII= angiotensin II; CV=cardiovascular; E=epinephrine; HF=heart failure; NE=norepinephrine; SNS=sympathetic nervous system Floras, JACC, 29, 34: Lymperopoulos et al. Circ Res 213;113:

2 RAAS: Initially compensatory and subsequently pathological in HF Landmark trials in HFrEF Angiotensinogen Renin Ang I ACEIs ACE ARBs AT 1 receptor Direct renin s CHARM-Alternative 3 (23) SOLVD-T 1 (1991) 2,28 patients 2,569 patients Candesartan (ARB) vs Enalapril (ACEI) vs 16% all-cause mortality 23% CV mortality or HF CIBIS-II 8 (1999) 2,647 patients Bisoprolol (BB) vs 34% all-cause mortality SHIFT 5 (21) 6,558 patients Ivabradine (I f ) vs 18% CV death or HF Signalling cascade 199s 2s 21s Biological actions hypertrophy secretion MRAs Na + /H 2O retention ADH Secretion Norepinephrine release Sympathetic tone MERIT-HF 2 (1999) 3991 patients Metoprolol vs 34% all-cause mortality CHARM-Added 4 (23) 2,548 patients Candesartan (ARB) vs 15% CV mortality or HF EMPHASIS-HF 6 (211) 2,737 patients Eplerenone (MRA) vs 37% CV mortality or HF Cardiac remodeling Myocyte necrosis Blood Pressure Blood volume Heart rate Contractility Studies ongoing; not approved for treatment of HF Zaman et al. Nat Rev Drug Discov 22;1:621 36; Schrier and Abraham. N Engl J Med 1999;341:577 85; Brewster et al. Am J Med ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme ; Sci 23;326:15 24; Schmieder. Am J Hypertens 25;18:72 3; McMurray et al. Eur Heart J 212;33: Francis et al. ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; MRA=mineralocorticoid receptor Ann Intern Med 1984;11:37 7; antagonist; RAAS=renin-angiotensin-aldosterone system Von Lueder et al. Circ Heart Fail 213;6: ACEI=angiotensin-converting enzyme ; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin ; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names 1. SOLVD Investigators. N Engl J Med 1991;325: MERIT-HF study group, Lancet, 1999, 353: Granger et al. Lancet 23;362: McMurray et al. Lancet 23;362: ; 5. Swedberg et al. Lancet 21;376: Zannad et al. N Engl J Med 211;364:11 21; 7. McMurray et al. N Engl J Med 214;371: CIBIS-II Investigators. Lancet 1999;353:9 13 Combination ACEI, -Blocker and MRA are now the cornerstone of therapy for HFrEF Neurohormonal Imbalance in Heart Failure ACEI +BB + MRA.44 (.26,.66) ACEI + ARB +BB.52 (.31,.8) ACEI +MRA.57 (.35,.91) ARB + BB.47 (.23,.86) ACEI + ARB.83 (.51, 1.24) ACEI + BB.57 (.41,.72) BB.57 (.33,.94) ARB.88 (.61, 1.26) ACEI.83 (.66, 1.1) HR (95% credible interval) for treatment vs. placebo HR<1 favors treatment Results are based on random-effects network meta-analysis using Bayesian models 2 Studies included: 57 RCTs, Phase II/III (Jan April 215) assessing guideline-recommended drug classes for HFrEF Excess vasodilation Compensation Excess vasoconstriction Endothelin Angiotensin II Vasopressin Norepinephrine Urocortin Patient population: Patients (aged 18 years) with chronic HFrEF (LVEF <45%) and NYHA class II IV of varying etiology presenting in the outpatient department were included 1. McMurray et al. Eur Heart J 212;33: ;.2. Burnett H et al. Circ Heart Fail. 217;1:e3529 Adapted from Shah M et al. Rev Cardiovasc Med. 21;2(suppl 2):S2 S6. 2

3 The Natriuretic Peptide Family Effects of the Natriuretic Peptides Cardiomyocytes 1 Endothelial cells 1 and H 2 N NPR-A NPR-B NPR-C H 2 N H 2 N Internalization Receptor recycling HOOC Vasodilation 1,2 HOOC HOOC Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 3 Myocardial relaxation 4,5 Diuresis, natriuresis 1,2 Antiapoptosis 6 Anti-aldosterone 1,2 Vasodilation 1,2 Degradation Antihypertrophy 1,2 of NPs 7 Antiproliferation 2 Vascular regeneration 1 Venodilation 1 Natriuretic peptide Antifibrosis 1 degradation and clearance Renin secretion inhibition 7 Reduced sympathetic tone 8 Lipolysis 7 Courtesy of Dr Ruskoaho 1. Mangiafico et al. Eur Heart J 213;34:886 93; 2. Gardner et al. Hypertension 27;49:419 26; 3. Yamahara et al., PNAS, 23, 1: Yamamoto et al.,ajp, 1997, 273: H Clarkson et al., Clin Science 1995: 88: Kasama et al., Eur. Heart. J. 28: 29: Volpe et al., Clin Science, 216: 13: Levin et al. N Engl J Med 1998;339; Effect of Short Term Augmentation of and Levels in HFrEF. Natriuretic peptides are cleared via NPR-C and degraded by the protease, neprilysin Short term NP infusion not associated with improvements in mortality or hospitalisation NPR-A Cardiomyocytes 1 and NPR-B Endothelial cells 1 NPR-C NEP cleavage products Longer term infusion or S/C treatment not feasible Receptor recycling Endocytosis Inhibition of Clearance a potential therapeutic target Vasodilation 1,2 Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 3 Myocardial relaxation 4,5 Diuresis, natriuresis 1,2 Antiapoptosis 6 Anti-aldosterone 1,2 Renin secretion inhibition 7 Vasodilation 1,2 Antihypertrophy 1,2 Antiproliferation 2 Vascular regeneration 1 Venodilation 1 Antifibrosis 1 Inactivation of NPs 7 Natriuretic peptide degradation and clearance Reduced sympathetic tone 8 Lipolysis 7 Lainchbury et al. Hypertension. 1999;34:7-75 Natriuretic peptide signaling and effects =atrial natriuretic peptide; =B-type natriuretic peptide; =C-type natriuretic peptide; =cyclic guanosine monophosphate; =guanosine triphosphate; NPR=neprilysin receptor 1. Mangiafico et al. Eur Heart J 213;34:886 93; 2. Gardner et al. Hypertension 27;49:419 26; 3. Yamahara et al., PNAS, 23, 1: Yamamoto et al.,ajp, 1997, 273: H Clarkson et al., Clin Science 1995: 88: Kasama et al., Eur. Heart. J. 28: 29: Volpe et al., Clin Science, 216: 13: Levin et al. N Engl J Med 1998;339;321 8;. 3

4 Plasma (pmol/l) Plasma (pmol/l) / Neutral Endopeptidase Cleavage Sites NEP is 749-AA, membrane-bound, zinc-dependent endopeptidase Found in epithelia, fibroblasts and neutrophils and in soluble form in the circulation, urine and CSF Widely present in kidneys, heart, brain, gut and lungs Antoni Bayes-Genis et al. JACC 216;68: and are degraded by neprilysin with similar levels of enzymatic efficiency is also degraded by neprilysin, but at a slower rate than and Antoni Bayes-Genis et al. JACC 216;68: Short-term NEP Inhibition in HFrEF Oral NEP inhibition elevates NP levels in patients with HF Candoxatril - an orally active of neprilysin Single oral doses of candoxatril increase and levels in seven patients with chronic HF 1# Before treatment After treatment mg 1 mg 5 mg 2 mg Dose of candoxatril mg 1 mg 5 mg 2 mg Dose of candoxatril # Seven patients (mean age 65) with chronic HF NYHA II III were given candoxatril 1, 5, 2 mg or placebo as a single dose in a four-way crossover study. Values as mean and SEM; p< 5 vs mg (placebo) (ANOVA); Lainchbury et al, J Clin Endocrinol Metab. 1999;84(2): 1. Lang et al. Lancet 1991;338:255 4

5 Proportion with event Proportion with event Oral NEP monotherapy failed to demonstrate clinical efficacy in HFrEF 1 Rationale for lack of efficacy with NEP monotherapy in HFrEF 1 Candoxatril showed minimal hemodynamic effects compared with placebo in patients with HFrEF 1-3 Left and right atrial pressures (reduced) Arterial pressures (no change) Heart rate (no change) Systemic or pulmonary vascular resistance (no change) Cardiac index (no change after exercise) Another neprilysin, ecadotril, led to numerically more deaths, as well as no evidence of clinical efficacy compared with placebo in patients with HF 2 Consequently, the development of both candoxatril and ecadotril for HF was discontinued 2 opposing actions of multiple neprilysin substrates increased levels offsetting beneficial effects of enhancing the NP system systemic vasoconstrictor rather than vasodilator effects (in part due to increased levels of the potent vasconstrictor ET-1) Natriuretic peptides Angiotensin II Angiotensin I Substance P Bradykinin Endothelin NEP fragments or metabolites Westheim et al. J Am Coll Cardiol 1999;34: ; 2. Cleland and Swedberg. Lancet 1998; 351: MaDowell and Nicholls, Cardiovasscular drug reviews, 2; 18: Westheim et al. J Am Coll Cardiol 1999;34: ; 2. Kimmelstiel et al. Cardiology 1996;87:46 53; 3. Kentsch et al. Eur J Clin Pharmacol 1996;51:269 72; 4. McDowell et al. Br J Clin Pharmacol 1997;43:329 32; 5. Ando et al. Hypertension 1995;26:116 6; 6. Von Lueder et al. Pharmacol Ther 214;144: 41 9; 7. Langenickel and Dole. Drug Discov Today:Ther Strateg 212;9:e inhibition must be accompanied by simultaneous RAAS blockade Angiotensinogen metabolizes Ang I and 1,2 Inhibition of neprilysin alone is associated with an increase in levels, counteracting the potential benefits of neprilysin inhibition 2 inhibition must be accompanied by simultaneous RAAS blockade Ang I Renin ACE AT 1 receptor Ang-(1 7) fragments Vasopeptidase s (dual NEP and ACE inhibition) showed promise in HFrEF The IMPRESS study, tested the efficacy and safety of omapatrilat compared with the ACEi lisinopril in 573 patients with HFrEF over 24 weeks.15 Death or admission for heart failure.15 Death, admission for heart failure, or discontinuation of treatment Signaling cascade.1 Lisinopril Omapatrilat p=.52.1 Lisinopril Omapatrilat p=.35 Biological actions.5.5 Na + /H 2O retention Norepinephrine release release Sympathetic tone 1. Von Lueder et al. Circ Heart Fail 213;6:594 65; 2. Langenickel and Dole. Drug Discov Today: Ther Strateg 212;9:e Time from randomization (days) Time from randomization (days) A randomized, double-blind, parallel trial in patients with chronic HF NYHA class II IV, LVEF 4%, and receiving an ACEI. Omapatrilat 4 mg (n=289) or lisinopril 2 mg (n=284) 1. Rouleau et al. Lancet 2;356:

6 Event-free survival (%) OVERTURE study showed trends towards efficacy with dual NEPi/ACEi but raised significant safety concerns Omapatrilat was compared with enalapril in 5,77 patients with HFrEF Time to death or HF 3 Omapatrilat Enalapril Months p= Omapatrilat discontinued due to: Lack of efficacy attributed to sub-optimal neprilysin and ACE inhibition over 24 hours due to the once-daily dosing regimen Safety concern unacceptable risk of angioedema (24 patients [.8%] vs 14 patients [.5%] for omapatrilat and enalapril, respectively)., attributed to dual neprilysin and ACE inhibition leading to elevated bradykinin levels, Co-inhibition of neprilysin and AT1-receptor: better efficacy with lower angioedema risk? Bradykinin is a substrate of neprilysin, ACE and other vasopeptidases Simultaneous inhibition of ACE and neprilysin results in elevated levels of bradykinin leading to higher risk of cough and angioedema 1,2 A selective neprilysin coupled with an ARB can enhance beneficial effects of NP system while inhibiting RAAS with minimal effect on bradykinin degradation 1 Omapatrilat inhibits ACE, APP and NEP 2 Selective NEP and ARB inhibition Active bradykinin Active bradykinin Bradykinin breakdown ACE APP NEP DPP-4 bradykinin bradykinin Packer et al.circulation 22;16: McMurray et al. Eur J Heart Fail 214;16:817 25; 2. Gu et al. J Clin Pharmacol 21;5: 41 14; Sacubitril/Valsartan a first in class dual neprilysin and AT1 receptor blocker Sacubitril/Valsartan is a salt complex comprised of two active components in a 1:1 molar ratio sacubitril (AHU377) a pro-drug metabolised to the neprilysin sacubitrilat valsartan an AT1 receptor blocker 3D sacubitril/valsartan structure 2 1. Bloch and Basile. J Clin Hypertens 21;12:89 12; 2. Gu et al. J Clin Pharmacol 21;5:41 14; 3. Langenickel and Dole. Drug Discov Today: Ther Strateg 212;9:e

7 Landmark trials in HFrEF CHARM-Alternative 3 (23) SOLVD-T 1 (1991) 2,28 patients 2,569 patients Candesartan (ARB) vs Enalapril (ACEI) vs 16% all-cause mortality 23% CV mortality or HF CIBIS-II 8 (1999) 2,647 patients Bisoprolol (BB) vs 34% all-cause mortality SHIFT 5 (21) 6,558 patients Isvabradine (I f ) vs 18% CV death or HF PARADIGM-HF 7 (214) 8,442 patients Sacubitril/valsartan (ARNI) vs enalapril: 199s 2s 21s MERIT-HF 2 (1999) 3991 patients Metorprolol vs 34% all-cause mortality CHARM-Added 4 (23) 2,548 patients Candesartan (ARB) vs 15% CV mortality or HF EMPHASIS-HF 6 (211) 2,737 patients Eplerenone (MRA) vs 37% CV mortality or HF ACEI=angiotensin-converting enzyme ; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin ; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names 1. SOLVD Investigators. N Engl J Med 1991;325: MERIT-HF study group, Lancet, 1999, 353: Granger et al. Lancet 23;362: McMurray et al. Lancet 23;362: ; 5. Swedberg et al. Lancet 21;376: Zannad et al. N Engl J Med 211;364:11 21; 7. McMurray et al. N Engl J Med 214;371: CIBIS-II Investigators. Lancet 1999;353:9 13 Sacubitril/valsartan development timelines in HFrEF Through its action of hydrolysis, NEP inhibition leads to natriuresis and diuresis First in class oral dual NEP and ACE s discovered but discontinued due to significant angioedema cases Largest HF trial in history compares sacubitril/valsartan to ACEi enalapril in HFrEF patients Sacubitril/valsartan (Entresto ) receives Australian TGA approval and is listed on the ARTG : NEP research : Omapatrilat and Angioedema : PARADIGM-HF study. Trial stopped early 2 Jan 216 TGA Approval The future : is discovered 25-26: Sacubitril/ valsartan is born 215: Sacubitril/ valsartan approval in US and EU 1 June 217 PBS Listing released by heart under stress conditions lowers the blood pressure Novartis develops a unique, well-defined crystalline salt complex comprising valsartan and sacubitrilat along with sodium ions and water. A proof of concept human study of sacubitril/valsartan in hypertension gives positive results Both ESC-HF and US guidelines give a recommendation of class IB and replacement of ACEi/ARB with sacubitril/valsartan in all symptomatic HFrEF patients Sacubitril/ valsartan is available on the PBS 1. de Bold AJ et al. Life Sci 1981;28:89 94; 2. Brauwald E et al, J Am Coll Cardiol 215;65:

8 Sacubitril/valsartan: inhibition combined with RAAS blockade is an alternative to an ACEI or ARB in patients with HFrEF 1 s NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin INACTIVE FRAGMENTS NP system HF SYMPTOMS & PROGRESSION Sacubitril/valsartan SNS Epinephrine α 1, β 1, β 2 Norepinephrine receptors RAAS activity Vasopressin Heart rate Contractility RAAS AT 1R Blood pressure Sympathetic tone β-blockers RAAS s (ACEI, ARB, MRA) ACEI=angiotensin-converting enzyme ; Ang=angiotensin; ARB=angiotensin receptor blocker; AT 1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system 1. McMurray et al. Eur J Heart Fail 213;15:162 73; 2. Minguet et al., Exp. Opin.Pharamacother, 215, 16:435-46;, Figure references: Levin et al. N Engl J Med 1998;339:321 8 degrades other vasoactive peptides substrates including NPR-A NPR-B NPR-C Ang I Bradykinin ET-1 Substance P cleavage products AT 1 receptor inhibition must be accompanied by simultaneous RAAS blockade Angiotensinogen metabolizes Ang I and 1,2 Inhibition of neprilysin alone is associated with an increase in Ang II levels, counteracting the potential benefits of neprilysin inhibition 2 inhibition must be accompanied by simultaneous RAAS blockade Ang I Renin ACE AT 1 receptor Ang-(1 7) fragments Endocytosis Inactivation of NPs 1,2,5 Receptor recycling Signaling cascades Biological actions Signaling cascade Vasodilation Cardiac fibrosis/hypertrophy Natriuresis/diuresis Cardiac fibrosis/hypertrophy Sodium/water retention Na + /H 2O retention release Norepinephrine release Sympathetic tone 1. Von Lueder et al. Circ Heart Fail 213;6:594 65; 2. Langenickel and Dole. Drug Discov Today: Ther Strateg 212;9:e

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